title: A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder.
abstract: BACKGROUND
  This study provides antimuscarinic agents for overactive bladder (OAB) display variable association with side effects mediated by the central nervous system (CNS), which may be of particular concern in the elderly. Adverse effects on CNS functioning are related to muscarinic receptor subtype selectivity and the ability of the agent to cross the blood-brain barrier, where P-gp plays a role in limiting permeability.
  
  
  CONCLUSIONS
  This study provides a parallel investigation of CNS penetration of antimuscarinic OAB agents in vivo and assessment of physical properties and permeability in cell monolayers in vitro. It adds further understanding of the roles of passive transcellular permeability and P-gp in determining CNS penetration of antimuscarinic OAB agents. It also enables a comparison of CNS side-effect profiles of OAB agents with preclinical CNS penetration data.
  
  
  OBJECTIVE
  To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents.
  
  
  METHODS
  Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays.
  
  
  RESULTS
  Oxybutynin displayed extensive CNS penetration, with brain:plasma ratios (B:P), unbound brain:unbound plasma ratios (Kp,free) and CSF:free plasma ratios each >1. Tolterodine (B:P = 2.95, Kp,free = 0.23 and CSF:free plasma = 0.16) and solifenacin (B:P = 3.04, Kp,free = 0.28 and CSF:free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B:P (0.03-0.16), Kp,free (0.01-0.04) and CSF:free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10(-6) cm s(-1) ), moderate for 5-HMT (11.7 × 10(-6) cm s(-1) ) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 × 10(-6) cm s(-1) ). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates.
  
  
  CONCLUSIONS
  Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study.
authors.affiliation: Pfizer Global Research & Development, Groton, CT Pfizer Inc, New York, NY, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Callegari
authors.forename: Bimal
authors.initials: B
authors.lastname: Malhotra
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bungay
authors.forename: Rob
authors.initials: R
authors.lastname: Webster
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Fenner
authors.forename: Sarah
authors.initials: S
authors.lastname: Kempshall
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: LaPerle
authors.forename: Martin C
authors.initials: MC
authors.lastname: Michel
authors.forename: Gary G
authors.initials: GG
authors.lastname: Kay
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics; D001572:Benzofurans / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003408:Cresols / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008333:Mandelic Acids / Q000493:pharmacokinetics; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics*; D010665:Phenylpropanolamine / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000493:pharmacokinetics; D011812:Quinuclidines / Q000493:pharmacokinetics; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism; D000069464:Solifenacin Succinate; D053719:Tandem Mass Spectrometry; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics; D000068737:Tolterodine Tartrate; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001559:Benzhydryl Compounds; D001572:Benzofurans; D003408:Cresols; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D044005:Tetrahydroisoquinolines; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C526675:fesoterodine; C101207:darifenacin; C005419:oxybutynin; D000069464:Solifenacin Succinate